Amyotrophic Lateral Sclerosis (Lou Gehrig's or Charcot's disease) is a progressive, incurable and fatal disease wherein the motor neurons degenerate at the spinal, bulbar and motor cortex level. In the case of Spain, incidence of the disease is 2/100,000 with a prevalence of 1/10,000, indicating that approximately 40,000 Spaniards will develop the disease in the course of their life (source: Spanish Association of Amyotrophic Lateral Sclerosis—ADELA—).
Despite having been recognized as a disease a long time ago, its causes are still unknown. Although there are genetic forms of the disease, there are also known cases where there does not appear to be a hereditary origin. Thus, it is estimated that 10% of cases, known as family forms, are of genetic origin, of which 15-20% correspond to mutations in the Super Oxide Dismutase enzyme (SOD-1). Mutations of this enzyme have also even been observed in sporadic forms of the disease (Brown, 1997). Mutations in the Neuro Filament Heavy-chain gene (NFH), have also been found unfrequently in some patients with amyotrophic lateral sclerosis. Consequently, research into the genetic inheritance of this disease is of great interest.
In recent years, the creation of animal models of the disease has become one of the most relevant tools in experimental treatment studies, serving to clarify some questions about its causes, although these causes are still largely unknown. Neither knockout mice for the SOD-1 enzyme, nor transgenic animals for the different mutations in the human SOD-1 enzyme have managed to reproduce similar clinical symptoms to the disease in humans. The animal that best approaches the progress of the disease in humans is a transgenic mouse, known as SOD1G93A, that presents various copies of mutant Super Oxide Dismutase with a Glycine to Alanine point mutation in amino acid 93, (Tu et al, 1996) which is supplied by The Jackson Laboratory,
Despite numerous studies carried out to understand the cause and mechanism of the disease, at this point, there are no classic effective treatments. Currently, three lines of research are under development based on the application of glutamate antagonists, neurotrophic factors, and antioxidants, even though to date none of them has lead to an efficient treatment.
For several years it has been known that neurotrophic factors are capable of rescuing motor neurons from degeneration. The experiences with gene therapy using adenoviral vectors that express various neurotrophic factors (e.g., GDNF, CNTF, NI-4, IGF-1) carried out on animal models have been of great interest, and have offered promising results. However, adenoviral injections present the disadvantage of having to be applied to neonatal animals due to the great immunity response that they elicit. Therefore, although these results have been promising, developing novel but less immunogenic vectors is imperative in order to provide an effective treatment for ALS.
In regard to the clinical tests carried out to date, those initiated in 1996 by Dr. Schuelp did not achieve satisfactory results (http://www.wiley.co.uk/genetherapy). Possible causes of this failure were the nature of the neurotrophic factor used in the tests (Ciliary Neurotrophic Factor; CNTF) and/or its lack of accessibility to the Central Nervous System. In 1999, Dr. Axel Kahn's group proved in model animals that the administration route of CNTF is an important factor for its therapeutic effect (Haase et al., 1999). This lack of specificity has also been proposed as the probable cause for the failure of the subcutaneous administration of BDNF (Bovine-Derived Neurotrophic Factor) to humans.
Moreover, when the neurotrophic factors are administered systemically they present toxicity problems by acting upon other tissues. Despite all of these disadvantages, the therapeutic possibilities of neurotrophic factors continue to be researched due to their promising pre-clinical results. Specifically, the latest clinical trial taking place in the Medical Center of Rochester (Minnesota) is based again on the administration of a neurotrophic factor, IGF-1 (Insulin-like Growth Factor 1)(Sakowshi et al., 2009).